title: Inverse agonist-like action of cadmium on G-protein-gated inward-rectifier K(+) channels.
abstract: The gate at the pore-forming domain of potassium channels is allosterically controlled by a stimulus-sensing domain. Using Cd²(+) as a probe, we examined the structural elements responsible for gating in an inward-rectifier K(+) channel (Kir3.2). One of four endogenous cysteines facing the cytoplasm contributes to a high-affinity site for inhibition by internal Cd²(+). Crystal structure of its cytoplasmic domain in complex with Cd²(+) reveals that octahedral coordination geometry supports the high-affinity binding. This mode of action causes the tethering of the N-terminus to CD loop in the stimulus-sensing domain, suggesting that their conformational changes participate in gating and Cd²(+) inhibits Kir3.2 by trapping the conformation in the closed state like "inverse agonist".
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan. inanobe@pharma2.med.osaka-u.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inanobe
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsuura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D054314:Drug Inverse Agonism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D013552:Swine; D014961:X-Ray Diffraction
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D002104:Cadmium; D003545:Cysteine